The functional impact of BRCA1 BRCT domain variants using multiplexed DNA double-strand break repair assays |
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Affiliation: | 1. Department of Biomedical Informatics, The Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA;2. Department of Genome Sciences, University of Washington and Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA;3. Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA |
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Abstract: | Pathogenic variants in BRCA1 are associated with a greatly increased risk of hereditary breast and ovarian cancer (HBOC). With the increased availability and affordability of genetic testing, many individuals have been identified with BRCA1 variants of uncertain significance (VUSs), which are individually detected in the population too infrequently to ascertain a clinical risk. Functional assays can be used to experimentally assess the effects of these variants. In this study, we used multiplexed DNA repair assays of variants in the BRCA1 carboxyl terminus to functionally characterize 2,271 variants for homology-directed repair function (HDR) and 1,427 variants for cisplatin resistance (CR). We found a high level of consistent results (Pearson’s r = 0.74) in the two multiplexed functional assays with non-functional variants located within regions of the BRCA1 protein necessary for its tumor suppression activity. In addition, functional categorizations of variants tested in the multiplex HDR and CR assays correlated with known clinical significance and with other functional assays for BRCA1 (Pearson’s r = 0.53 to 0.71). The results of the multiplex HDR and CR assays are useful resources for characterizing large numbers of BRCA1 VUSs. |
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Keywords: | BRCA1 breast cancer ovarian cancer variant classification DNA repair functional assays BRCT domain variants of uncertain significance |
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